As in other cancers, melanoma is a heterogenous tumor. There are several subsets, one of which is Spitzoid melanoma. Spitzoid melanoma clinically and histopathologically resembles a benign melanocytic neoplasm called Spitz nevus. The diagnosis of these tumors can be difficult in some cases and as a result there is substantial evidence of misdiagnoses that lead to fatal outcomes. Therefore, there is a need to identify molecular markers to differentiate these tumors and predict outcome. Oncogenic mutations in NRAS and BRAF leading to activation of the Ras-ERK pathway play a role in melanoma. NRAS mutations are found in 10% and BRAF mutations in 60% of conventional melanomas. Our previous studies show that Spitz nevi lack and Spitzoid melanomas harbor infrequent mutations (3.5%) in BRAF. No mutations in NRAS are found in Spitz tumors. However, the majority of the Spitzoid melanomas (87%) in our series show ERK activation, suggesting that in Spitzoid melanomas Ras-ERK activation occurs through genetic events distinct from other melanomas. Our hypothesis is that Spitz nevi and Spitzoid melanomas have unique molecular signatures that distinguish these tumors. In this study, we will examine Spitz nevi and Spitzoid melanoma tumor samples for DNA copy number changes by array based comparative genomic hybridization (a-CGH). This technique is ideally suited to delineate genomic differences of histologically similar tumors with differing clinical behaviors. To date, we have collected a unique set of Spitz nevi, primary and metastatic Spitzoid melanoma samples with clinical outcome data. First, we anticipate identifying molecular signatures based on a-CGH that can distinguish Spitzoid melanoma from Spitz nevi. These studies will aid in accurate diagnosis and classification of Spitzoid tumors. Second, in order to define prognostic criteria, we will correlate selected markers from a-CGH analysis of Spitzoid melanomas with clinical and histopathologic parameters such as age, gender, tumor site, tumor thickness, ulceration, and sentinel lymph node status. Finally, we will evaluate the contribution of known melanoma genes to Spitzoid melanoma pathogenesis. The studies in this application are the first steps towards a molecular based understanding of Spitzoid melanoma and include exploratory studies for molecular diagnosis and outcome prediction.